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Issue 9, 2002
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Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides as novel NMDA receptor antagonists having a unique NMDA receptor subtype selectivity

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Abstract

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b), which is a conformationally restricted analog of the antidepressant milnacipran [(±)-1], is a new class of potent NMDA (N-methyl-D-aspartic acid) receptor antagonists. A series of analogs of 2b modified at the 1′-position were designed and synthesized starting from (R)-epichlorohydrin via the key intermediate an optically active cyclopropanecarbaldehyde derivative 8 with a (1S,2R)-configuration. Among these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-enyl]-N,N-diethylcyclopropanecarboxamide (2i) and (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-ynyl]-N,N-diethylcyclopropanecarboxamide (2j) were identified as more potent NMDA receptor antagonists than 2b. The subtype selectivity of 2i and 2j together with 2b was investigated to show that 2i inhibited the GluRε3/ζl and GluRε4/ζl subtypes four times more strongly than GluRε1/ζl and GluRε2/ζl subtypes. Compound 2i is the first GluRε3/ζl and GluRε4/ζl subtype-selective antagonist, while the selectivity is not so high.

Graphical abstract: Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides as novel NMDA receptor antagonists having a unique NMDA receptor subtype selectivity

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Publication details

The article was received on 18 Dec 2001, accepted on 08 Mar 2002 and first published on 04 Apr 2002


Article type: Paper
DOI: 10.1039/B111540P
J. Chem. Soc., Perkin Trans. 1, 2002, 1199-1212

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    Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides as novel NMDA receptor antagonists having a unique NMDA receptor subtype selectivity

    Y. Kazuta, R. Tsujita, S. Uchino, N. Kamiyama, D. Mochizuki, K. Yamashita, Y. Ohmori, A. Yamashita, T. Yamamoto, S. Kohsaka, A. Matsuda and S. Shuto, J. Chem. Soc., Perkin Trans. 1, 2002, 1199
    DOI: 10.1039/B111540P

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